DESCRIPTION (Investigator's Abstract): In the search for new and more effective drugs, a large number of small peptides and peptide-like compounds (3-10 amino acids) have been discovered. Many of these compounds demonstrate significant pharmacologic activity. However, because peptidic compounds tend to be poorly absorbed when administered orally, identifying an oral delivery method with high systemic bioavailability is key to allow for wide usage and acceptance of these compounds. This application proposes that by coupling peptides to bile acids, these compounds can be transported by the ileal bile acid transporter resulting in a significantly improved oral bioavailability. However, for the method to be successful, an understanding of the chemical and spatial requirements of the ileal bile acid transporter is needed. Additionally, the stability of the peptide- bile acid conjugates and the influence of other transporters upon the net uptake of the conjugates need to be defined, and methods that will separate the active compound from the bile acid backbone upon absorption need to be devised. The specific aims of this research plan are to synthesize and study the transport, as well as the mechanism for rapid systemic release of these compounds via use of labile linkers. Transport of a variety of conjugates will be studied both in cell cultures and in vivo. By appropriately coupling the results with computer analysis of the structure-transport relationship, the applicants hope to be able to determine the chemical and spatial requirements necessary for transport. Separation of the active compound from the bile acid backbone will be studied using in vitro and in vivo methods. By fully exploring the nature of the ileal bile acid transporter and of peptide - bile acid conjugates, novel strategies to improve bioavailabiltiy of peptides and more fully realize the potential of these compounds to treat a variety of diseases may be devised.